The average degrees of predicted recombination-induced folding disruption in the gp120 and Nef proteins are appreciably higher than those predicted in the other HIV-1 proteins for which extensive high resolution structural data is available. Consistent with the notion that these proteins may be particularly sensitive to recombination-induced folding disruption is the fact that, in actual BIHC HIV-1M recombinants, breakpoints only very rarely occur at sites where they are anticipated to have a maximally disruptive effect on the folding of these proteins. A plausible explanation for gp120 and Nef being particularly sensitive to recombination-induced folding disruption relative to the other HIV-1M proteins examined here, is that they are less conserved than these other proteins and recombinant versions of gp120 and Nef will therefore tend to have many more potentially disruptive amino acid combinations. In order to more rigorously test whether the chimaeric proteins that are expressed by HIV-1M recombinants tend to display lower degrees of protein folding disruption than can be accounted for under random recombination in the absence of selection against misfolded protein chimaeras, individual HIV-1M proteins were analysed using a previously described permutation-based ����avoidance of protein folding disruption���� test. Similar to the findings of a recent study using an alternative approach to that described here, we found that in five out of the eight analysed proteins, intra-protein amino acid interactions in chimaeric proteins expressed by natural HIV-1M recombinants are inferred to have been significantly less disrupted than could be accounted for by chance. The main difference between our result and that of is that we did not detect any evidence of avoidance of protein folding disruption in the protease protein. Although three of the eight proteins analysed here displayed no detectable signal of lower than expected recombination-induced fold disruption, in at least one case, this may simply be due to low numbers of recombination breakpoints having been detected Sephin1 within the gene encoding this protein: a fact which reduces our ability to detect a signal in this protein.